((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid → Carbon dioxide methanol

HRID 12607

반응식

HRID 12607 반응식
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:18][C:19]([OH:21])=[O:20])[C:12]=2[N:11]([C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH2:23][CH2:24][CH3:25])[CH:10]=1.[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:52]2[CH2:51][CH2:50][CH2:49][C@H:48]([CH2:53][C:54]([OH:56])=[O:55])[C:47]=2[N:46]([C@@H:57]([C:61]2[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=2)[CH2:58][CH2:59][CH3:60])[CH:45]=1>>[C:19](=[O:21])=[O:20].[CH3:54][OH:55].[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:52]2[CH2:51][CH2:50][CH2:49][C@H:48]([CH2:53][C:54]([OH:56])=[O:55])[C:47]=2[N:46]([C@H:57]([C:61]2[CH:62]=[CH:63][C:64]([C:67]([F:69])([F:70])[F:68])=[CH:65][CH:66]=2)[CH2:58][CH2:59][CH3:60])[CH:45]=1.[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:18][C:19]([OH:21])=[O:20])[C:12]=2[N:11]([C@@H:22]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH3:25])[CH:10]=1

참가 물질

5

반응물 2

HCID 68707990((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acidHCID 68709637HCID 68709637, 화합물

생성물 3

HCID 21973728Carbon dioxide methanolHCID 68707990((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acidHCID 68710213HCID 68710213, 화합물

실험 절차

Prepared as described for Example 1, using 2,4-dichloro-beta-nitrostyrene in Step 2 with heating at 200° C. in a microwave apparatus; m/z (ES−) 522 (M−H+). The enantiomers and diastereomers could be separated by supercritical fluid chromatography. A CHIRALPAK AD-H column 250×10 mm (5μ) Column temperature 40° C., Mobile phase: 85/15 CO2/MeOH, Flow rate: 10 mL/min, outlet pressure 100 bar gave pure Example 2a ((7S)-3-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 5.50 min 1H NMR δ (ppm) (CDCl3): 7.55 (2 H, d, J=8.2 Hz), 7.46 (1 H, d, J=2.0 Hz), 7.29 (1 H, s), 7.22 (1 H, dd, J=2.1, 8.3 Hz), 7.14 (2 H, d, J=8.1 Hz), 7.04 (1 H, s), 5.14 (1 H, dd, J=6.3, 9.0 Hz), 3.04 (1 H, s), 2.66 (2 H, d, J=6.7 Hz), 2.42 (2 H, t, J=3.7 Hz), 2.24-2.16 (1 H, m), 2.11-2.04 (1 H, m), 1.81-1.66 (5 H, m), 1.42 (1 H, dd, J=0.0, 6.6 Hz), 1.21 (3 H, d, J=6.1 Hz), 1.01 (3 H, t, J=7.3 Hz), a mixture of Example 2b ((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid and Example 2c ((7R)-3-(2,4-dichlorophenyl)-1-{(1S-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 6.25 min and finally pure Example 2d ((7R)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 7.35 min 1H NMR δ (ppm) (CDCl3): 7.55 (2 H, d, J=8.2 Hz), 7.46 (1 H, d, J=2.0 Hz), 7.29 (1 H, s), 7.22 (1 H, dd, J=2.1, 8.3 Hz), 7.14 (2 H, d, J=8.1 Hz), 7.04 (1 H, s), 5.14 (1 H, dd, J=6.3, 9.0 Hz), 3.04 (1 H, s), 2.66 (2H, d, J=6.7 Hz), 2.42 (2 H, t, J=3.7 Hz), 2.24-2.16 (1 H, m), 2.11-2.04 (1 H, m), 1.81-1.66 (5 H, m), 1.42 (1 H, dd, J=0.0, 6.6 Hz), 1.21 (3 H, d, J=6.1 Hz), 1.01 (3 H, t, J=7.3 Hz). The mixture of Example 2b and Example 2c were separated by further SFC purification using a CHIRALCEL OJ-H column 250×10 mm (5μ) Column temperature 40° C., Mobile phase: 80/20 CO2/MeOH, Flow rate: 10 mL/min, outlet pressure 100 bar gave Example 2b ((7R)-3-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 3.04 min 1H NMR δ (ppm)(CDCl3): 7.59 (2 H, d, J=8.1 Hz), 7.46 (1 H, d, J=1.8 Hz), 7.32 (2 H, d, J=8.1 Hz), 7.30 (1 H, d, J=8.3 Hz), 7.22 (1 H, dd, J=8.3, 1.8 Hz), 6.96 (1 H, s), 5.18 (1 H, t, J=7.6 Hz), 3.38 (1 H, d, J=8.5 Hz), 2.48-2.43 (2 H, m), 2.29 (1 H, dd, J=11.0, 15.6 Hz), 2.12-2.06 (2 H, m), 2.03 (1 H, d, J=15.6 Hz), 1.88-1.76 (3 H, m), 1.68 (1 H, m), 1.38-1.30 (2 H, m), 0.96 (3 H, t, J=7.3 Hz) and Example 2c ((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl] butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 4.13 min 1H NMR δ (ppm)(CDCl3): 7.59 (2 H, d, J=8.1 Hz), 7.46 (1 H, d, J=1.8 Hz), 7.32 (2 H, d, J=8.1 Hz), 7.30 (1 H, d, J=8.3 Hz), 7.22 (1 H, dd, J=8.3, 1.8 Hz), 6.96 (1 H, s), 5.18 (1 H, t, J=7.6 Hz), 3.38 (1 H, d, J=8.5 Hz), 2.48-2.43 (2 H, m), 2.29 (1 H, dd, J=11.0, 15.6 Hz), 2.12-2.06 (2 H, m), 2.03 (1 H, d, J=15.6 Hz), 1.88-1.76 (3 H, m), 1.68 (1 H, m), 1.38-1.30 (2 H, m), 0.96 (3 H, t, J=7.3 Hz).

후처리

  1. customThe mixture of Example 2b and Example 2c were separated by further SFC purification
  2. customa CHIRALCEL OJ-H column 250×10 mm (5μ) Column temperature 40° C., Mobile phase

출처 및 근거

ORD 기록
ord-0407c9fe77f041d9bd525224435cc5c6
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07728022B2

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